Cysteine proteases represent an enzymatic class of proteins that catalyze the hydrolysis of peptide bonds by a nucleophilic sulfhydryl group of a cysteine residue in the active site of the enzyme. Several normal and disease processes in mammals have been associated with cysteine protease activity and include, but are not limited to: osteoporosis, osteoarthritis (Inui, T., O. Ishibashi, et al. J Biol Chem 1997, 272(13), 8109-12; Saftig, P., E. Hunziker, et al. Adv Exp Med Biol 2000+ADs 2000, 477, 293-303; Saftig, P., E. Hunziker, et al. Proc Natl Acad Sci U S A 1998, 95(23), 13453-8), periodontal diseases, Paget's disease, atherosclerosis (Jormsjo, S., D. M. Wuttge, et al. Am J Pathol 2002 161(3), 939-45), multiple sclerosis (Beck, H., G. Schwarz, et al. Eur J Immunol 2001, 31(12), 3726-36), rheumatoid arthritis (Nakagawa, T. Y., W. H. Brissette, et al. Immunity 1999, 10(2), 207-17; Hou, W. S., Z. Li, et al. Am J Pathol 2001, 159(6), 2167-77), juvenile onset diabetes, lupus, asthma (Cimerman, N., P. M. Brguljan, et al. Pflugers Arch 2001, 442(6 Suppl 1), R204-6), tissue rejection, Alzheimer's disease (Lemere, C. A., J. S. Munger, et al. Am J Pathol 1995, 146(4), 848-60), Parkinson's disease (Liu, Y., L. Fallon, et al. Cell 2002, 111(2), 209-18), neuronal degeneration, shock (Jaeschke, H., M. A. Fisher, et al. J Immunol 1998, 160(7), 3480-6), cancer (Fernandez, P. L., X. Farre, et al. Int J Cancer 2001, 95(1), 51-5), malaria (Malhotra, P., P. V. Dasaradhi, et al. Mol Microbiol 2002, 45(5), 1245-54), Chagas (Eakin, A. E., A. A. Mills, et al. J Biol Chem 1992, 267(11), 7411-20), leishmaniasis, shistosomiasis, and African trypanosomiasis (Caffrey, C. R., S. Scory, et al. Curr Drug Targets 2000, 1(2), 155-62; Lalmanach, G., A. Boulange, et al. Biol Chem 2002, 383(5), 739-49).
Cathepsins are a subclass of cysteine protease that belong to the enzyme classification EC 3.4.22 (Barrett, A. J., N. D. Rawlings, et al. Handbook of proteolytic enzymes. London, Academic Press). Cathepsins play a major role in lysosomal, endosomal, and extracellular protein degradation and have thus been implicated in many disease processes. For example, Cathepsin B [EC 3.4.22.1] has been postulated to play a role in tumor metastasis (Berquin, I. M. and B. F. Sloane Adv Exp Med Biol 1996, 389, 281-94).
Cathepsin S [EC 3.4.22.27] is largely expressed in professional antigen presenting cells such as macrophages and dendritic cells. Cathepsin S has been shown to be required for proper MHC class II antigen presentation (Shi, G. P., J. A. Villadangos, et al. Immunity 1999, 10(2) 197-206). As a result of its non-redundant role in MHC class II antigen presentation, cathepsin S has been associated with inflammation, arthritis, and atherosclerosis. The selective expression of cathepsin K [EC 3.4.22.38] in osteoclasts coupled with the ability of cathepsin K to degrade type I collagen suggests that it plays a role in normal and pathogenic bone remodeling (Bromme, D., K. Okamoto, et al. J Biol Chem 1996, 271(4), 2126-32). There is a need in the art for compounds and methods that selectively inhibit specific cysteine proteases for treating several pathogenic disorders in mammals. The present invention satisfies these and other needs.